STRUCTURAL FEATURES OF CHEMICALLY TRANSMITTING SYNAPSES

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This chapter discusses the structural features of chemically transmitting synapses. The motor axon loses its myelin sheath quite close to the branching of the terminal by which it expands to make a series of discrete contacts with a specialized region of the muscle fiber: the motor endplate. There are numerous vesicles about 500 Å in diameter in the presynaptic terminal, and they tend to collect in groups at sites on the presynaptic membrane fronting the cleft, particularly in proximity to the junctional folds. The synaptic endings on the somas of the Purkinje cells of the cerebellum are from the basket cells. Likewise, the synapses on the somas of hippocampal pyramidal cells are from the hippocampal basket cells. In less than a decade, electron microscopy has provided a clear picture of the main structures that are required for physiological explanations of chemical transmission at synapses.

Examination by light-microscopy discloses very great diversity in the various types of chemically transmitting synaptic contacts, e.g. the neuromuscular junctions of vertebrates, the various types of synapses in different regions of the central nervous system of vertebrates, the synapses in sympathetic ganglia, the giant synapses in the squid stellate ganglion, the synapses in neuropiles of invertebrates, the synapses of electric organs. The higher order of magnification given by electron-microscopy reveals that in these diverse types of synapse there is a remarkable uniformity in the structures which are believed to be essentially concerned in their functional operation. The review by COUTEAUX (1961) gives a particularly valuable correlation between structural features and physiological events. It will be convenient firstly to illustrate these features by an account of the vertebrate neuromuscular junction, which has been more thoroughly investigated than any other synapse.

A The vertebrate neuromuscular junction

Fig. 1A shows diagrammatically the ultimate achievement of light microscopy (COUTEAUX 1958). The motor axon loses its myelin sheath quite close to the branching of the terminal by which it expands to make a series of discrete contacts (3 in Fig. 1A) with a specialized region of the muscle fibre, the motor endplate. These terminal axonal branches have a much denser mitochondrial content than the axon and he partly embedded in shallow troughs on the surface of the motor endplate. The motor endplate is characterized by an accumulation of sarcoplasm in which are embedded many nuclei and mitochondria. By differential staining it has been established that a continuous membrane is interposed between the axoplasm and the sarcoplasm, and on the deep surface of this membrane there is a regular structure appearing in Fig. 1A as small rods arranged perpendicularly, the subneural apparatus. Also shown in Fig. 1A is a teloglial or Schwann cell (tel.) with its prominent nucleus on the upper surface of the nerve terminal. An important additional observation is that by histochemical identification the acetylcholine-esterase (AChE) is associated with the subneural apparatus and remains after degeneration of the nerve terminal (KOELLE and FRIEDENWALD 1949; COUTEAUX and TAXI 1952; DENZ 1953; COUTEAUX 1958). The conclusion that the location of AChE is on the muscle fibre and not on the nerve terminal is fully substantiated by electron-microscopy, which identifies the subneural apparatus with the junctional folds of the muscle surface membrane (Fig. 1B).

Fig. 1A and B A. Schematic drawing of a motor endplate. ax., axoplasm with its mitochondria; my., myelin sheath; tel., teloglia (terminal Schwann cells); sarc., sarcoplasm with its mitochondria; m.n., muscle nuclei; mf., myofibrils. The terminal nerve branches lie in “synaptic gutters” or “troughs”. Immediately under the interface axoplasm-sarcoplasm, the ribbon-shaped subneural lamellae, transversely cut, may be seen as rodlets (COUTEAUX 1958). B. Tracing of a longitudinal section of a frog neuro-muscular junction, × 19,000. The line of the synaptic cleft between the nerve ending and the muscle is indicated by the arrows. Note the junctional folds of the synaptic cleft extending into the muscle. Four mitochondria (Mit.) are shown surrounded by double lines. SF denotes one of the “Schwann finger” extensions of the Schwann cell (seen above the nerve ending) into the synaptic cleft (BIRKS, HUXLEY and KATZ 1960)

There have been several very thorough electron-microscopic studies of neuromuscular junctions of amphibia, reptiles and mammals (PALADE and PALAY 1954; ROBERTSON 1956, 1960; REGER 1958; ANDERSON-CEDERGREN 1959; BIRKS, HUXLEY and KATZ 1960), and it is now well established that all have the essential structure which is illustrated in Fig. 1B from a longitudinal section of an amphibian neuromuscular junction. We may regard this as a higher magnification of the element in Fig. 1A between the arrows. Correspondingly, there are the Schwann cell on the upper surface of the nerve terminal, the mitochondria in the nerve terminal and the subneural apparatus or junctional folds projecting into the sarcoplasm from the junctional region. But the much higher resolution reveals in addition two structural features which are of great functional importance and which characterize all chemically transmitting synapses.

Firstly, as indicated by the arrows in Fig. 1B, there is a cleft of about 500 Å width completely separating the surface membranes of the nerve terminal and the motor endplate. In Fig. 1B an unusual number of fine teloglial processes (Schwann fingers, SF) have intruded into the synaptic cleft, but otherwise the nerve membrane is freely exposed to the muscle membrane across the cleft, being separated only by the contents of the cleft which is thought to have a fluid or thin gel consistency (PALAY 1958), and which is seen to contain in Fig. 1B an opaque central band that extends down into the junctional folds. At the edge of the neural contact the synaptic cleft opens into the extracellular space.

Secondly, there are numerous vesicles about 500 Å in diameter in the presynaptic terminal, and they tend to collect in groups at sites on the presynaptic membrane fronting the cleft, particularly in proximity to the junctional folds. There is much indirect evidence to suggest that these synaptic vesicles represent packets of the transmitter substance (Chapter III). Consequently several functional problems can be formulated, though as yet none is satisfactorily answered: the mode of production of vesicles; the control of their movement up to the synaptic cleft; the way in which a nerve impulse effects a release of their contents into the cleft; their subsequent fate after extrusion of contents.

Additional features revealed by electron-microscopy are the coverage of the nerve terminal by the Schwann cell except where it is embedded in the troughs of the motor endplate (cf. Fig. 1B), and the fact that the junctional folds are formed by folding of the surface membrane of the muscle fibre, so including, as noted above, a space communicating with the synaptic cleft and apparently filled by the same material.

Thus in summary the structure of the neuromuscular junction has a structural design that is very efficient for the operation of a chemically transmitting synapse. The synaptic vesicles tend to be aggregated close to the synaptic cleft so that they are readily available for releasing their contents into the cleft. Once released into the cleft the transmitter substance should rapidly diffuse to and act on the subjacent muscle membrane. The ionic fluxes so generated could cause a flow of electrical current from the adjacent surface of the muscle fibre through the extracellular spaces and in through the cleft to the subsynaptic membrane of the muscle fibre. The junctional folds increase the effective area of this membrane, and hence its electrical conductance, by a factor of about three. The location of AChE on the cleft side of the junctional folds ensures that it is optimally sited for hydrolysing the transmitter, acetylcholine, and so for terminating its action.

B Synapses of the mammalian central nervous system

In less than a decade electron-microscopy has enormously advanced our knowledge of synapses in the central nervous system. There is a remarkable degree of agreement in the essential features of synapses as described by the three principal groups of investigators under the leaderships of DE ROBERTIS, PALAY and GRAY, as may be seen by reference to their review articles (DE ROBERTIS 1958, 1959A; PALAY 1958; WHITTAKER and GRAY 1962). Thus, as illustrated in the microphotographs and in the drawings of various types of synapses (Figs. 2 and 3), the presynaptic fibre ends in an...